Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5.
The human Mixed-Lineage-Leukemia-5 (MLL5) gene is located in a genomic region frequently deleted in patients with myeloid malignancies and encodes a widely expressed nuclear protein most closely related to MLL1, a Trithorax transcriptional regulator with established involvement in leukemogenesis. Although the physiologic function of MLL5 is completely unknown, domain structure and homology to transcriptional regulators with histone methyltransferase activity suggest a role in epigenetic gene regulation. To investigate physiologic functions of Mll5, we have generated a knockout mouse mutant using Cre/loxP technology. Adult homozygous Mll5-deficient mice are obtained at reduced frequency because of postnatal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth, and defects in multiple hematopoietic lineages. Interestingly, Mll5(-/-) mice die of sublethal whole-body irradiation but can be rescued with wild-type bone marrow grafts. Flow cytometric ana-lysis, bone marrow reconstitution, and in vivo BrdU-labeling experiments reveal numerical, functional, and cell-cycle defects in the lineage-negative Sca-1(+), Kit(+) (LSK) population, which contains short- and long-term hematopoietic stem cells. Together, these in vivo findings establish several nonredundant functions for Mll5, including an essential role in regulating proliferation and functional integrity of hematopoietic stem/progenitor cells.
Madan
Vikas
V
Institute of Immunology, University Clinics Ulm, Ulm, Germany.
Madan
Babita
B
Brykczynska
Urszula
U
Zilbermann
Frédéric
F
Hogeveen
Kevin
K
Döhner
Konstanze
K
Döhner
Hartmut
H
Weber
Odile
O
Blum
Carmen
C
Rodewald
Hans-Reimer
HR
Sassone-Corsi
Paolo
P
Peters
Antoine H F M
AH
Fehling
Hans Jörg
HJ
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005804:Genes, Lethal; D006130:Growth Disorders / Q000235:genetics* / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D007248:Infertility, Male / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011247:Pregnancy; D011836:Radiation Tolerance / Q000235:genetics
D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C539231:MLL5 protein, mouse